Researchers at UC Berkeley have found a weakness within triple-negative breast cancer, which has long been a form of cancer that is extremely hard to combat. A molecule similar to a drug has been used to both kill cancer cells within the lab and shrink tumors in mice.
Associate professor of chemistry, nutritional sciences and toxicology at UC Berkeley, Daniel K. Nomura, was the senior author in this new study. He says the team was looking for targets that lead to the metabolism of cancer in this aggressive form of cancer.
One in five breast cancers are traced back to the triple-negative form. This type of cancer is one of the deadliest forms of breast cancer because there are not currently any drugs available that are able to target these types of tumors. What makes this cancer so dangerous is that it does not feed off of estrogen, progesterone or the human epidermal growth factor receptor 2 (known as HER2) as other types of the disease do. Modern medicine targets those areas in the body, making this cancer a difficult battle to face. Chemotherapies from the past are often used to treat the cancer while it remains in the breast, but once it starts to spread elsewhere, treatment solutions are minimal.
During this new study, researchers looked for active enzymes which triple-negative breast cancers use uniquely during metabolism. As observations continued, it was found that this dangerous form of cancer relies on high activity by the enzyme glutathione-S-transferase Pi1 (or GSTP1). GSTP1 works by regulating glycolysis metabolism, leading to an impairment of glycolytic metabolism within cells damaged by triple-negative cancer. This damage appears as minimal energy, a decrease in nutrients and ability to carry out regular signals. Cells within tumors leach on to glycolysis.
Eranthie Weerapana, associate professor of chemistry at Boston College, built a molecule called LAS17 that attaches itself permanently to the GSTP1 molecule, preventing future activity. LAS17 completely ignores other protein cells and has not shown any virulent side effects but did successfully shrink tumors. Upcoming research includes continued testing on the LAS17 molecule and a closer look at tumor tissue that has been taken from humans and transplanted into mice.
Nomura says inhibiting GSTP1 greatly impairs glycolytic metabolism, starving triple-negative breast cancer cells and making it impossible for them to create the needed macromolecules. Thanks to GSTP1, lipids are not built that assist in the creation of membranes and nucleic acids that are required to create new DNA do not appear. The molecules cannot create the amount of energy necessary to functioning when GSTP1 stops them from making large amounts of the ATP molecule.
The latest findings have paved the way for drug development strategies, says Nomura, who was very surprised that a single target came from the team’s search. The team used a method known as reactivity-based chemoproteomics which is a quick way to find the Archilles’ heels of proteins. Their hope is to locate protein targets that are active within cells, versus observing all genes in order to locate the specific genes that have started the process of creating more protein. With the help of chemical probes, Nomuar’s team was able to pinpoint configurations of amino acids cysteine and lysine, which play important roles in the growth of proteins.
Nomura believes it is much more effective to focus on fully grown proteins than those which are in the earliest stages of development, as a lot can change during their maturation. So far GSTP1 is the only metabolically active enzyme that only appeared in instances where triple-negative breast cancer cells were present.
The complete study was published in online journal Cell Chemical Biology on May 12th, 2016.